Elite suppressors are HIV-1 infected patients who maintain viral loads of <50 copies/ml without antiretroviral therapy. We have recently shown for the first time that replication competent virus can be isolated from some of these individuals suggesting that immunologic control of replication competent HIV-1 is possible. The mechanism of control has yet to be defined in these patients, but we have shown that superior humoral immunity is not the cause of control in many ES and neither is an intrinsic resistance to HIV-1 infection. We have shown that provirus from these patients also do not have higher levels of APOBEC 3G/F mediated hypemutation. Taken together it appears that superior HIV-specific cellular immunity plays a key role in the control of viremia in elite suppressors. While the mechanism of CD8+ T cell mediated control is unkown, it has been shown that elite suppressors and patients with progressive disease have similar frequencies of HIV-specific CTL. However, it has recently been shown that unstimulated CD8+ T cells from elite suppressors, but not patients with progressive disease, are able to control the replication of a laboratory strain of HIV-1 in autologous CD4+ T cells. This is a physiological model since the CD8+ T cells are not activated prior to being used in the assay and the CD4+ T cells process and present HIV antigens (as opposed to peptides being added to the cells in culture). The objective of this proposal is to determine the mechanisms by which this CD8+ T cell mediated control of this replication competent virus is achieved. We plan to determine whether CD8+ T cells are capable of controlling HIV replication in macrophages and whether they can kill these target cells when they are productively infected. We also plan to determine whether CD4+ T cells are capable of suppressing viral replication in macrophages and CD4+ T cells by direct killing activity or by cytokine secretion. Finally we will determine whether effector CD4+ and CD8+ T cells are capable of killing latently infected CD4+ T cells This work will be important for the development of vaccines that can be used to improve the HIV specific immune responses in HIV-1 infected individuals. This may allow some patients to control the virus without antiretroviral therapy for prolonged periods of time. This will also have major implications for strategies for HIV-1 eradication since clearance of latently infected cells is facilitated by effecor T cell responses.